Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Am J Hum Genet. 2019 Jun 6;104(6):1210-1222. doi: 10.1016/j.ajhg.2019.03.021. Epub 2019 May 9.
We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
我们基于 36 个家庭中的 38 个人，描绘了一种与 KMT2E 相关的神经发育障碍。该研究包括 31 种不同的 KMT2E 杂合变异（其中 28 种从 Matchmaker Exchange 中确定，3 种以前有报道过），以及 4 种包含 KMT2E 的 7q22.2-22.23 号染色体微缺失个体（其中 1 种以前有报道过）。几乎所有的变异都是新生的，而且大多数是截断的。大多数携带蛋白质截断变异的受影响个体表现出轻度智力残疾。四分之一的个体符合自闭症标准。其他常见的特征包括大头畸形、低张力、功能性胃肠道异常和微妙的面部整体形态。大约五分之一的截断变异个体患有癫痫，几乎所有的癫痫都对抗癫痫药物治疗有反应。超过 70%的个体是男性，而且男女的表达性是可变的；女性癫痫更常见，男性自闭症更常见。这四个包含 KMT2E 的微缺失个体的表现与截断变异个体大致相同，但发育迟缓的程度更大。这四个 KMT2E 错义变异个体的表现与截断变异个体的表现最为严重，所有个体都患有癫痫，通常表现为治疗抵抗的婴儿癫痫性脑病。大头畸形在这一组中也很常见。KMT2E 中的错义变异可能导致功能丧失或显性负效应，这可能解释了表型的这种差异，但需要独立验证。KMT2E 的破坏变异是神经发育异常的一个未被充分认识的原因。
